The present invention relates to dialysis and more particularly to methods of supplementing dialysate solutions for the prevention or treatment of iron deficiency in hemodialysis and peritoneal dialysis patients.
Patients with chronic renal failure are treated by dialysis. Dialysis is required to maintain homeostasis in patients with end stage kidney failure. Dialysis is defined as the movement of solute and water through a semipermeable membrane which separates the patients blood from the dialysate solution. The semipermeable membrane can either be the peritoneal membrane in peritoneal dialysis patients or an artificial dialyzer membrane in hemodialysis patients.
Patients with chronic renal failure suffer from anemia due to impaired production of erythropoietin [Erslev, 1991]. Clinical manifestations of chronic renal failure improve as uremia and volume overload are corrected by dialysis. However, anemia due to lack of erythropoietin becomes a major limiting factor in the functional well being of end stage renal disease patients.
Molecular cloning of the erythropoietin gene [Jacobs, et al., 1985] led to commercial production of recombinant erythropoietin, which was a major advance in the treatment of renal anemia [Erslev, 1991; Levin, 1992]. Erythropoietin therapy functions by stimulating red cell production and thereby iron utilization. With the use of erythropoietin therapy, transfusions are avoided in most chronic dialysis patients. Blood tests and gastrointestinal bleeding further contribute to loss of iron. Therefore, accelerated iron utilization coupled with small but unavoidable loss of extra corporeal blood with hemodialysis and increased gastrointestinal losses of iron lead to iron deficiency in almost all patients on long term maintenance dialysis.
Other factors that may contribute to an iron deficient state are the restricted renal diet which may be deficient in iron, and iron absorption may be impaired by uremia per se. Co-administration of additional medications, such as phosphate binders with food, may also impair iron absorption. Therefore, iron deficiency has become a major problem in the dialysis patients treated with erythropoietin.
In clinical practice transferrin saturation (ratio of serum iron to total iron binding capacity) and serum ferritin are used to assess the iron status. The majority of maintenance dialysis patients receiving erythropoietin therapy can be arbitrarily classified into six groups depending on their iron status (Table 1).
In states of iron deficiency, iron supply to bone marrow is not maintained and the response to erythropoietin is impaired. Indeed, iron deficiency is the most common cause of erythropoietin resistance [Kleiner et al., 1995]. Uremic patients suffering from absolute or functional iron deficiency require lower doses of erythropoietin if they receive effective iron supplementation. Based on these considerations, Van Wyck et al., [1989] have suggested that all renal patients with low to normal iron stores should prophylactically receive iron. Iron supplementation is accomplished most conveniently by the oral administration of iron one to three times a day.
A problem exists because oral iron is often not tolerated due to gastrointestinal side effects. Practical problems such as noncompliance, impaired absorption when taken with meals, and other factors are further combined with the problem of tolerating oral iron. It is also ineffective due to impaired iron absorption. Macdougall et al.,[1989] also found a retarded response to recombinant human erythropoietin in hemodialysis patients on oral iron, which was corrected once iron was given intravenously. Schaefer and Schaefer [1995], have recently demonstrated that only intravenous but not oral iron, guarantees adequate marrow iron supply during the correction phase of recombinant erythropoietin therapy.
In Europe, iron is available for intravenous administration as iron dextran, iron saccharate and iron gluconate. In the United States, only iron dextran is approved for intravenous use and is widely used for this purpose in dialysis patients. However, there are controversies with regard to the dosage and frequency of injection.
On the one hand, intravenous iron therapy has several advantages over oral administration. Intravenous therapy overcomes both compliance problems and the low gastrointestinal tolerance often observed in patients on oral therapy. Schaefer and Schaefer [1992] reported a 47% reduction in erythropoietin dose when intravenous iron was given to iron deficient hemodialysis patients previously treated with oral iron. On the other hand, intravenous iron therapy does have risks and disadvantages. Anaphylactoid reactions have been reported in patients [Hamstra et al., 1980; Kumpf et al., 1990]. Therefore, a test dose must be administered when parenteral iron therapy is first prescribed. Intravenous iron therapy can also cause hypotension, and loin and epigastric pain during dialysis which may be severe enough to stop the treatment. Further, the intravenous drug is expensive and requires pharmacy and nursing time for administration. With intravenous iron therapy, serum iron, transferrin and ferritin levels have to be regularly monitored to estimate the need for iron and to measure a response to the therapy. Finally, there is also a concern about potential iron overload with intravenous therapy, since the risk of infection and possibly cancer are increased in patients with iron overload [Weinberg, 1984]. Recent evidence further suggests a 35% higher risk for cause-specific infectious deaths in US Medicare ESRD patients given intravenous iron frequently [Collins et al., 1997].
In view of the above, neither the oral nor intravenous iron therapy route is ideal and alternative routes of iron administration are desirable for dialysis patients. The hypotensive effects of intravenous iron dextran are completely abolished, irrespective of the total dose administered, by reducing the rate of infusion or by preliminary dilution of the iron dextran with isotonic saline [Cox et al., 1965]. Addition of an iron compound to the hemodialysis or peritoneal dialysis solutions should lead to a slow transfer of iron into the blood compartment if the dialysis membrane is permeable to the iron salt. Colloidal iron compounds or iron in its mineral form are not soluble in aqueous solutions and therefore not suitable for addition to the dialysate. Furthermore, iron is known to be toxic when administered parenterally in its mineral form. The toxic effects may arise from precipitation of iron in the blood, producing multiple pulmonary and sometimes systemic emboli. Symptoms resembling that of fat embolism occur. Irritation of the gastrointestinal tract gives rise to diarrhea and vomiting. Also, depression of the central nervous system can lead to coma and death [Heath et al., 1982].
Very few noncolloidal iron compounds are suitable for intravenous administration. In the last five years, at least two groups of researchers have administered ferric gluconate sodium intravenously for the treatment of iron deficiency in chronic hemodialysis patients [Pascual et al., 1992; Allegra et al., 1981]. In these and various other studies, solubility, bioavailability and toxicity of various ferric compounds were shown to be different.
Recent studies have shown that polyphosphate compounds are possible candidates for intracellular iron transport [Konopka et al., 1981; Pollack et al., 1985]. Among these polyphosphate compounds, pyrophosphate has been shown to be the most effective agent in triggering iron removal from transferrin [Pollack et al., 1977; Morgan, 1979; Carver et al., 1978]. Pyrophosphate has also been shown to enhance iron transfer from transferrin to ferritin [Konopka et al., 1980]. It also promotes iron exchange between transferrin molecules [Morgan, 1977]. It further facilitates delivery of iron to isolated rat liver mitochondria [Nilson et al., 1984].
Ferric pyrophosphate has been used for iron fortification of food and for oral treatment of iron deficiency anemia [Javaid et al., 1991]. Ferric pyrophosphate has also been used for supplying iron to eukaryotic and bacterial cells, grown in culture [Byrd et al., 1991]. Toxic effects of ferric pyrophosphate have been studied by Maurer and coworkers in an animal model [19901]. This study showed an LD50 slightly higher than 325 mg of ferric pyrophosphate per kilogram or approximately 35 milligrams of iron per kilogram body weight. The effective dose for replacing iron losses in hemodialysis patients is estimated to be 0.2 to 0.3 milligrams iron per kilogram per dialysis session. Therefore, the safety factor (ratio of LD50 to effective dose) is over 100.
Another metal pyrophosphate complex, stannous pyrophosphate has been reported to cause hypocalcemia and immediate toxic effects. Since ferric ion forms a stronger complex to pyrophosphate than do stannous ion, or calcium ion, [Harken et al., 1981; Sillen et al., 1964], hypocalcemia is not a known side affect of ferric pyrophosphate administration.
The U.S. Pat. No. 4,756,838 to Veltman, issued Jul. 12, 1988, discloses a dry, free flowing, stable readily soluble, noncaking, particulate soluble products which are readily soluble in water and are useful for preparing solutions for use in hemodialysis. The patent discloses the fact that currently used dialysis procedures do not ordinarily take into account those materials in blood that are protein bound. Examples are iron, zinc, copper, and cobalt. The patent states that it is an object of the invention to make such materials as an integral part of dry dialysate products. However, no specific disclosure is made on how to make the iron available through the hemodialysis. No direction is given towards a noncolloidal iron compound as opposed to any other iron compound or mineral iron.
In view of the above, it is desirable to administer iron to a large proportion of dialysis patients by adding a soluble, noncolloidal iron compound to dialysis solutions, in order to replace ongoing losses of iron or to treat iron deficiency. This soluble, noncolloidal iron compound is preferably ferric pyrophosphate.
In accordance with the present invention, there is provided a method of administering iron in dialysis patients by infusion of a noncolloidal ferric compound, soluble in dialysis solutions, by the process of dialysis. The present invention further provides a pharmaceutical composition consisting essentially of a dialysis solution including a soluble, noncolloidal ferric compound. Preferably, the ferric compound is ferric pyrophosphate.